TOWARD IMAGING GLYCOTOOLS BY CLICK COUPLING - Click Chemistry in Glycoscience: New Developments and Strategies - page 199

FmocHN COOH

AcO
AcO
AcO

AcO
AcO
AcO

FmocHN COOH

O

O

BF 3 -Et 2 O
CH 3 CN, 80 °C
5 min.

+

OAc

O R

HO R

18 F

18 F

98 R = H, CH 3 100

33% HBr
AcOH

AcO
AcO
AcO

AcO
AcO
AcO

FmocHN COOH

FmocHN COOH AgOTf

CH 2 Cl 2, rt

O

O

+

Br

O

18 F

HO

18 F

2 min.

101 102

SCHEME 7.22 Glycosylation as a click coupling reaction between FDG and protected
serine or threonine derivatives.

(Scheme 7.22) [96]. The best Lewis acid was BF 3 -Et 2 O in acetonitrile as the
best solvent. It is interesting to note that the reaction was performed at 80 ◦ C and
proceeded in good radiochemical yield to give 100 . N -glycosylation of lysine amino
group cannot be achieved this way.
In a comparative study, the same group proposed the use of Koenigs-Knorr con-
ditions [97]. Acetylated [ 18 F]FDG 98 was converted into the corresponding bromide
101 by treatment with 33% HBr/AcOH for 5 minutes. Glycosylation of Fmoc-Ser-
OH was then achieved using silver triflate as the promoter in dichloromethane to give
102 in about 21% radiochemical yield together with the corresponding glycosyl ester.
It is interesting to note that the reaction proceeded in 67% radiochemical yield with
Z-Ser-OBn. From these results, it is clear that this methodology cannot be applied to
peptide having unprotected carboxylic residues.

7.4.4 Disulfide Formation

Dissymmetrical disulfide bond formation introduced by Davis [98] may be regarded
as a click reaction as it proceeds rapidly and with high selectivity in aqueous medium.
A good example of the ligation of activated [ 18 F]FDG thioglycosides with cysteine
containing peptides has been reported (Scheme 7.23) [99]. On treatment of 98 under
classical bromination conditions, the radioactive bromide 101 wasformedin20min-
utes in about 65% radiochemical yield. The phenylthiosulfonate formation was stud-
ied in detail and the use of a mixture of acetonitrile/DMF (4:1) at 70 ◦ C for 20 minutes
gave the best corrected radiochemical yield (33%) in thioglycoside 103 . The coupling
reaction with c(RGDfC) peptide proceeded rapidly in 50 mM tris buffer (pH 7.7) at
room temperature for 15 minutes to give 104 in up to 95% radiochemical yield. This
conjugate was found to be stable in human serum at 37 ◦ C.